Abstract:

The discovery of microRNAs (miRNAs - small non-coding RNAs of ~22 nt) heralded a new and exciting era in biology. During this period miRNAs have gone from ignominy due to their origin mainly in ‘junk DNA’ to notoriety where they can be at once characterized as being all powerful (a single miRNA can target and potentially silence several hundred genes) and yet marginal (a given gene can be targeted by several miRNAs such that a given miRNA typically exerts a modest repression) [1-4]. The emerging paradox is exemplified by miRNAs that are prominently expressed in embryonic stem (ES) cells. The collective importance of miRNAs is firmly established by the fact that Dicer-/- mouse embryos die on day 7.5 due to defects in differentiation [5]. However, oppositely correlated expression that is expected of conventional repressors is increasingly being defied in multiple systems in relation to miRNA-mRNA target pairs. This is most evident in ES cells where miR-290-295 and 302 clusters the most abundant ES cell miRNAs, are both found to be driven by pluripotency genes Oct4, Nanog and Sox2 and are predicted to target Sox2 in ‘incoherent feed-forward loops’ [7]. Here the miRNAs are co-expressed and positively correlated with these targets that they repress suggesting that one of their primary roles is to fine tune gene expression rather than act as ON/OFF switches. On the other hand, let-7 family members that are notably low in ES cells and rapidly induced upon differentiation exhibit more conventional anticorrelated expression patterns with their targets [7, 8]. In an intricately designed auto-regulatory loop, LIN28, a key ‘keeper’ of the pluripotent state binds and represses the processing of let-7 (a key ‘keeper‘ of the differentiated state) [9-11]. One of the let-7 family members, let-7g targets and represses LIN28 through four 3-UTR binding sites [12]. We propose that LIN28/let-7 pair has the potential to act as a ‘toggle switch’ that balances the decision to maintain pluripotency vs. differentiation. We also propose that the c-Myc/E2F driven miR17-92 cluster that together controls the G1 to S transition is fundamental for ES self-renewal and cell proliferation [13-18]. In that context it is no surprise that LIN28 and c-Myc (and therefore let-7 and miR-17-92 by association) and more recently Oct4/Sox2 regulated miR-302 has been shown to be among a handful of factors shown to be necessary and sufficient to convert differentiated cells to induced pluripotent stem (iPS) cells [19-29]. It is also no surprise that activation of miR-17-92 (OncomiRs) and down-regulation of let-7 (tumor suppressors) is a recurring theme in relation to cancers from multiple systems [30-48]. We speculate that the LIN28/let-7; c-MYC-E2F/miR-17-92 and Oct4/Sox2/miR-302-cyclin D1 networks are fundamental to properties of pluripotency and self-renewal associated with embryonic stem cells. We also speculate that ES cell miRNA-mRNA associations may also regulate tissue homeostasis and regeneration in the fully developed adult. Consequently, the appropriate regulation of LIN28/let-7; c-MYC-E2F/miR-17-92 and Oct4/Sox2/miR-302-cyclin D1 gene networks will be critical for the success of regenerative strategies that involve iPS cells. Perturbations in any of the key ES cell miRNA-mRNA networks maybe a hallmark of cancer stem cells (CSCs).

Abstract: The discovery of microRNAs (miRNAs - small non-coding RNAs of ~22 nt) heralded a new and exciting era in biology. During this period miRNAs have gone from ignominy due to their origin mainly in ‘junk DNA’ to notoriety where they can be at once characterized as being all powerful (a single miRNA can target and potentially silence several hundred genes) and yet marginal (a given gene can be targeted by several miRNAs such that a given miRNA typically exerts a modest repression) [1-4]. The emerging paradox is exemplified by miRNAs that are prominently expressed in embryonic stem (ES) cells. The collective importance of miRNAs is firmly established by the fact that Dicer-/- mouse embryos die on day 7.5 due to defects in differentiation [5]. However, oppositely correlated expression that is expected of conventional repressors is increasingly being defied in multiple systems in relation to miRNA-mRNA target pairs. This is most evident in ES cells where miR-290-295 and 302 clusters the most abundant ES cell miRNAs, are both found to be driven by pluripotency genes Oct4, Nanog and Sox2 and are predicted to target Sox2 in ‘incoherent feed-forward loops’ [7]. Here the miRNAs are co-expressed and positively correlated with these targets that they repress suggesting that one of their primary roles is to fine tune gene expression rather than act as ON/OFF switches. On the other hand, let-7 family members that are notably low in ES cells and rapidly induced upon differentiation exhibit more conventional anticorrelated expression patterns with their targets [7, 8]. In an intricately designed auto-regulatory loop, LIN28, a key ‘keeper’ of the pluripotent state binds and represses the processing of let-7 (a key ‘keeper‘ of the differentiated state) [9-11]. One of the let-7 family members, let-7g targets and represses LIN28 through four 3-UTR binding sites [12]. We propose that LIN28/let-7 pair has the potential to act as a ‘toggle switch’ that balances the decision to maintain pluripotency vs. differentiation. We also propose that the c-Myc/E2F driven miR17-92 cluster that together controls the G1 to S transition is fundamental for ES self-renewal and cell proliferation [13-18]. In that context it is no surprise that LIN28 and c-Myc (and therefore let-7 and miR-17-92 by association) and more recently Oct4/Sox2 regulated miR-302 has been shown to be among a handful of factors shown to be necessary and sufficient to convert differentiated cells to induced pluripotent stem (iPS) cells [19-29]. It is also no surprise that activation of miR-17-92 (OncomiRs) and down-regulation of let-7 (tumor suppressors) is a recurring theme in relation to cancers from multiple systems [30-48]. We speculate that the LIN28/let-7; c-MYC-E2F/miR-17-92 and Oct4/Sox2/miR-302-cyclin D1 networks are fundamental to properties of pluripotency and self-renewal associated with embryonic stem cells. We also speculate that ES cell miRNA-mRNA associations may also regulate tissue homeostasis and regeneration in the fully developed adult. Consequently, the appropriate regulation of LIN28/let-7; c-MYC-E2F/miR-17-92 and Oct4/Sox2/miR-302-cyclin D1 gene networks will be critical for the success of regenerative strategies that involve iPS cells. Perturbations in any of the key ES cell miRNA-mRNA networks maybe a hallmark of cancer stem cells (CSCs).